Canavan disease (CD), or spongy degeneration of brain, is an autosomal recessive leukodystrophy associated with mental retardation, megalencephaly, hypotonia and death, usually in the first decade of life. Brain histology in CD is characterized by spongy degeneration of white matter with astrocytic swelling and elongated mitochondria1-5. Canavan disease is more prevalent in Jewish people of Ashkenazi origin3-5. Matalon et al. (1988) described aspartoacylase deficiency as the basic biochemical defect in CD6. Since the initial report, 145 patients have been diagnosed with CD a single center, suggesting that CD is more prevalent than previously thought10-12. Aspartoacylase deficiency in CD has also been reported by other investigators13,14.
The deficiency of aspartoacylase in CD leads to excessive excretion of NAA in urine and its accumulation in brain6,9-11. Aspartoacylase in brain has been localized to white matter associated with myelin tracks16. How aspartoacylase and the hydrolysis of NAA are involved in keeping white matter intact is not clear. It is also not understood how the deficiency of aspartoacylase leads to the pathogenesis seen in CD.
Aspartoacylase has been purified and characterized from bovine brain and from other bovine and human sources16. Biochemical and immunochemical studies suggest that aspartoacylase has been conserved during evolution. Aspartoacylase activity has been found in a variety of mammalian tissues, including kidney, brain white matter, adrenal glands, lung, liver and cultured skin fibroblasts. Brain grey matter and blood constituents do not have any detectable aspartoacylase activity (Kaul et al., unpublished studies).
Aspartoacylase specifically hydrolyses N-acetyl-L-aspartic acid (NAA) to aspartate and acetate7,8. Stereospecificity of aspartoacylase towards L-analog of NAA has been well documented. The D-analog of NAA acts as a weak inhibitor of NAA hydrolysis by aspartoacylase. Studies have suggested that the carbon backbone of NAA is involved in interaction with the substrate binding site of aspartoacylase; and that the substitutions at α and β carboxyl groups of aspartate moiety do not have any effect on hydrolysis of NAA by aspartoacylase16.
The diagnosis of CD is now routinely made by quantitation of NAA in urine and estimation of aspartoacylase activity in cultured skin fibroblast12. The level of aspartoacylase activity found in direct chorionic villi cells or in cultured chorionic villi cells and amniocytes is about 2 orders of magnitude lower than that found in normal cultured skin fibroblasts. Due to the low aspartoacylase activity in chorionic villi cells and amniocytes, the prenatal diagnosis of CD using aspartoacylase assay is not satisfactory15.
Due to the devastating nature of this genetic disease, there is an urgent need for better diagnostic methods for early detection of the disease, both pre- and postnatally, and screening methods to detect genetic carriers of the disease to allow informed genetic counseling for prospective parents. Additionally, there is a critical need for an effective treatment, and even more preferably, a cure for the underlying biochemical defect.